A Humeral Osteosarcoma Mimicking Osseous Leiomyosarcoma: A Case Report.

Osteosarcoma stands as one of the primary mesenchymal bone neoplasms commonly encountered in clinical practice. This malignancy often presents with a wide range of distinctive imaging characteristics. Here, we present a unique case wherein a delayed diagnosis of high-grade osteosarcoma occurred due to the absence of an osteoid matrix in the initial imaging studies. A 61-year-old female, initially presented with a left humeral fracture. As the healing of the fractured bone was delayed and the possibility of a pathologic fracture was considered, a CT-guided biopsy was performed. Histological examination of the biopsy sample initially suggested an osseous leiomyosarcoma. The lack of osteoid matrix on radiographs including aggressive intra-medullary mass seen on MRI, combined with the patient's age, appeared consistent with a diagnosis of leiomyosarcoma of bone. As a result, the initial diagnosis was not called into question. Due to neurovascular involvement, this led to a forequarter amputation. However, upon microscopic examination of the amputation specimen, certain areas exhibited features indicative of malignant osteoid deposition, ultimately supporting a revised diagnosis of high-grade osteosarcoma. This case underscores the critical importance of considering the limitations of core biopsy samples, especially when dealing with suspected limb masses associated with pathological fractures. Radiographs and CT scans can prove invaluable in ruling out subtle adjacent osteoid, and ultimately a multidisciplinary approach to the diagnosis of osteosarcoma is imperative to ensure accurate identification.

Tibial osteochondroma with thick cartilage which mimicked a chondrosarcoma: A case report.

We report a case of tibial osteochondroma in a 25-year-old female who presented with a palpable calf mass. This mass was associated with a thick cartilaginous cap on cross-sectional imaging, suggesting chondrosarcoma. A CT-guided biopsy was performed, and histology, however, was consistent with osteochondroma. Orthopedic oncology recommended surgical excision due to the potential high sampling error with chondroid lesions. The patient underwent surgical resection, resulting in a final diagnosis of osteochondroma. No post-surgical complications occurred, and a 12-month follow-up showed no evidence of local recurrence. This case highlights the atypical imaging feature of a thick cartilaginous cap in a benign etiology without malignant transformation.

5-Hydroxypyrroloindoline Affords Tryptathionine and 2,2'-bis-Indole Peptide Staples: Application to Melanotan-II.

With peptides increasingly favored as drugs, natural product motifs, namely the tryptathionine staple, found in amatoxins and phallotoxins, and the 2,2'-bis-indole found in staurosporine represent unexplored staples for unnatural peptide macrocycles. We disclose the efficient condensation of a 5-hydroxypyrroloindoline with either a cysteine-thiol or a tryptophan-indole to form a tryptathionine or 2-2'-bis-indole staple. Judicious use of protecting groups provides for chemoselective stapling using α-MSH, which provides a basis for investigating both chemoselectivity and affinity. Both classes of stapled peptides show nanomolar Ki's, with one showing a sub-nanomolar Ki value.

Diphenylphosphinylhydroxylamine (DPPH) Affords Late-Stage S-imination to access free-NH Sulfilimines and Sulfoximines.

Sulfilimines, as potential aza-isosteres of sulfoxides, are valued as building blocks, auxiliaries, ligands, bioconjugation handles, and as precursors to versatile S(VI) scaffolds including sulfoximines and sulfondiimines. Here, we report a thioether imination methodology that exploits O-(diphenylphosphinyl)hydroxyl amine (DPPH). Under mild, metal-free, and biomolecule-compatible conditions, DPPH enables late-stage S-imination on peptides, natural products, and a clinically trialled drug, and shows both excellent chemoselectivity and broad functional group tolerance. This methodological report is extended to an efficient and high-yielding one-pot reaction for accessing free-NH sulfoximines with diverse substrates including ones of potential clinical importance. In the presence of a rhodium catalyst, sulfoxides are S-iminated in higher yields to afford free-NH sulfoximines. S-imination was validated on an oxidatively delicate amatoxin to give sulfilimine and sulfoximine congeners. Interestingly, these new sulfilimine and sulfoximine-amatoxins show cytotoxicity. This method is further extended to create sulfilimine and sulfoximine-Fulvestrant and buthionine analogues.

Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies.

Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment strategies. Later, we focus on chemotherapy strategies for this childhood sarcoma and discuss the impact of three mechanisms that are involved in the chemotherapy response including apoptosis, macro-autophagy, and the unfolded protein response. Finally, we discuss in vivo mouse and zebrafish models and in vitro three-dimensional bioengineering models of rhabdomyosarcoma to screen future therapeutic approaches and promote muscle regeneration.

Toward tryptathionine-stapled one-bead-one-compound (OBOC) libraries: solid phase synthesis of a bioactive octretoate analog.

New somatostatin analogs are highly desirable for diagnosing and treating neuroendocrine tumors (NETs). Here we describe the solid-phase synthesis of a new octreotate (TATE) analog where the disulfide bond is replaced with a tryptathionine (Ttn) staple as part of an effort to prototyping a one-bead-one-compound (OBOC) library of Ttn-stapled peptides. Library design provides the potential for on- and off-bead screening. To validate our method, we labelled Ttn-TATE with a fluorescent dye to demonstrate binding to soluble somatostatin receptor subtype-2 and staining of Ar42J rat prostate cancer cells. By exploring this staple in the context of a ligand of known affinity, this method paves the way for an OBOC library construction of bioactive octreotate analogs and, more broadly speaking, tryptathionine-staped peptide macrocycles.

[Drugs: minors and harm reduction?] / Drogues : mineur-e-s et réduction des risques ?

The use of controlled substances (narcotics and psychotropic substances) poses increased risks for minors. However, minors are generally excluded from existing harm reduction services (e.g. drug consumption rooms, drug checking, exchange of consumption material). Based on public health considerations, the authors recommend the establishment of harm reduction services for minors.

La consommation de substances soumises à contrôle (stupéfiants et substances psychotropes) présente des risques accrus pour les mineur-e-s. Pourtant, ces derniers sont généralement exclus des offres existantes de réduction des risques et des méfaits (par exemple, locaux de consommation, drug checking, échange de matériel de consommation). Sur la base de considérations de santé publique, les auteurs recommandent la création de services de réduction des risques dédiés aux mineur-e-s.

The "Ins and Outs" of Prostate Specific Membrane Antigen (PSMA) as Specific Target in Prostate Cancer Therapy.

Prostate-specific membrane antigen (PSMA) is expressed in epithelial cells of the prostate gland and is strongly upregulated in prostatic adenocarcinoma, with elevated expression correlating with metastasis, progression, and androgen independence. Because of its specificity, PSMA is a major target of prostate cancer therapy; however, detectable levels of PSMA are also found in other tissues, especially in salivary glands and kidney, generating bystander damage of these tissues. Antibody target therapy has been used with relative success in reducing tumor growth and prostate specific antigen (PSA) levels. However, since antibodies are highly stable in plasma, they have prolonged time in circulation and accumulate in organs with an affinity for antibodies such as bone marrow. For that reason, a second generation of PSMA targeted therapeutic agents has been developed. Small molecules and minibodies have had promising clinical trial results, but concerns about their specificity had arisen with side effects due to accumulation in salivary glands and kidneys. Herein we study the specificity of small molecules and minibodies that are currently being clinically tested. We observed a high affinity of these molecules for PSMA in prostate, kidney and salivary gland, suggesting that their effect is not prostate specific. The search for specific prostate target agents must continue so as to optimally treat patients with prostate cancer, while minimizing deleterious effects in other PSMA expressing tissues.

Machine learning and reduced order modelling for the simulation of braided stent deployment.

Endoluminal reconstruction using flow diverters represents a novel paradigm for the minimally invasive treatment of intracranial aneurysms. The configuration assumed by these very dense braided stents once deployed within the parent vessel is not easily predictable and medical volumetric images alone may be insufficient to plan the treatment satisfactorily. Therefore, here we propose a fast and accurate machine learning and reduced order modelling framework, based on finite element simulations, to assist practitioners in the planning and interventional stages. It consists of a first classification step to determine a priori whether a simulation will be successful (good conformity between stent and vessel) or not from a clinical perspective, followed by a regression step that provides an approximated solution of the deployed stent configuration. The latter is achieved using a non-intrusive reduced order modelling scheme that combines the proper orthogonal decomposition algorithm and Gaussian process regression. The workflow was validated on an idealized intracranial artery with a saccular aneurysm and the effect of six geometrical and surgical parameters on the outcome of stent deployment was studied. We trained six machine learning models on a dataset of varying size and obtained classifiers with up to 95% accuracy in predicting the deployment outcome. The support vector machine model outperformed the others when considering a small dataset of 50 training cases, with an accuracy of 93% and a specificity of 97%. On the other hand, real-time predictions of the stent deployed configuration were achieved with an average validation error between predicted and high-fidelity results never greater than the spatial resolution of 3D rotational angiography, the imaging technique with the best spatial resolution (0.15 mm). Such accurate predictions can be reached even with a small database of 47 simulations: by increasing the training simulations to 147, the average prediction error is reduced to 0.07 mm. These results are promising as they demonstrate the ability of these techniques to achieve simulations within a few milliseconds while retaining the mechanical realism and predictability of the stent deployed configuration.

Imidazolium-methylene-trifluoroborate: A novel radioprosthetic group validated with preclinical 18 F-Positron Emission Tomography imaging of Prostate Specific Membrane Antigen in mice.

Organotrifluoroborates have gained acceptance as radioprosthetic groups for radiofluorination. Of these, the zwitterionic prosthetic group "AMBF3 " with a quaternary dimethylammonium ion dominates the trifluoroborate space. Herein, we report on imidazolium-methylene trifluoroborate (ImMBF3 ) as an alternative radioprosthetic group and report on its properties in the context of a PSMA-targeting EUK ligand that was previously been conjugated to AMBF3 . The ImMBF3 is readily synthesized from imidazole and conjugated via CuAAC "click" chemistry to give a structure similar to PSMA-617. 18 F-labeling proceeded in one step per our previous reports and imaged in LNCaP-xenograft bearing mice. The [18 F]-PSMA-617-ImMBF3 tracer proved to be less polar (LogP7.4 = -2.95 ± 0.03) while showing a significantly lower solvolytic rate (t1/2 = 8100 min) and slightly higher molar activity (Am) at 174 ± 38 GBq/µmol. Tumor uptake was measured at 13.7 ± 4.8%ID/g and a tumor:muscle ratio of 74.2 ± 35.0, tumor:blood ratio of 21.4 ± 7.0, tumor:kidney ratio of 0.29 ± 0.14, and tumor:bone ratio of 23.5 ± 9.5. In comparison with previously reported PSMA-targeting EUK-AMBF3 conjugates, we have altered the LogP7.4 value, tuned the solvolytic half-life of the prosthetic, and increased radiochemical conversion while achieving similar tumor uptake, contrast ratios, and molar activities compared with AMBF3 bioconjugates.

Salt Metathesis: Tetrafluoroborate Anion Rapidly Fluoridates Organoboronic Acids to give Organotrifluoroborates.

Tetrafluoroborate (BF4 - ) has long been used as a spectator counter anion. Herein, we report an unprecedented salt metathesis between a variety of BF4 - salts and a series of organoboronic acids yielding the corresponding organotrifluoroborates. We identified conditions for fast and efficient fluoridation (<1 h) with minimal workup. Fundamentally, this work discloses the proclivity of BF4 - to exchange fluoride atoms with organoboronates, highlighting the lability of BF4 - .

Rationally Designed Amanitins Achieve Enhanced Cytotoxicity.

For 70 years, α-amanitin, the most cytotoxic peptide in its class, has been without a synthetic rival; through synthesis, we address the structure-activity relationships to inform the design of new amatoxins and disclose analogues that are more cytotoxic than the natural product when evaluated on CHO, HEK293, and HeLa cells, whereas on liver-derived HepG2 cells, the same toxins show diminished cytotoxicity.

Synthesis and preliminary evaluation of octreotate conjugates of bioactive synthetic amatoxins for targeting somatostatin receptor (sstr2) expressing cells.

Targeted cancer therapy represents a paradigm-shifting approach that aims to deliver a toxic payload selectively to target-expressing cells thereby sparing normal tissues the off-target effects associated with traditional chemotherapeutics. Since most targeted constructs rely on standard microtubule inhibitors or DNA-reactive molecules as payloads, new toxins that inhibit other intracellular targets are needed to realize the full potential of targeted therapy. Among these new payloads, α-amanitin has gained attraction as a payload in targeted therapy. Here, we conjugate two synthetic amanitins at different sites to demonstrate their utility as payloads in peptide drug conjugates (PDCs). As an exemplary targeting agent, we chose octreotate, a well-studied somatostatin receptor (sstr2) peptide agonist for the conjugation to synthetic amatoxins via three tailor-built linkers. The linker chemistry permitted the evaluation of one non-cleavable and two cleavable self-immolative conjugates. The immolating linkers were chosen to take advantage of either the reducing potential of the intracellular environment or the high levels of lysosomal proteases in tumor cells to trigger toxin release. Cell-based assays on target-positive Ar42J cells revealed target-specific reduction in viability with up to 1000-fold enhancement in bioactivity compared to the untargeted amatoxins. Altogether, this preliminary study enabled the development of a highly modular synthetic platform for the construction of amanitin-based conjugates that can be readily extended to various targeting moieties.

Selection of M2+ -Independent RNA-Cleaving DNAzymes with Side-Chains Mimicking Arginine and Lysine.

Sequence-specific cleavage of RNA by nucleic acid catalysts in the absence of a divalent metal cation (M2+ ) has remained an important goal in biomimicry with potential therapeutic applications. Given the lack of functional group diversity in canonical nucleotides, modified nucleotides with amino acid-like side chains were used to enhance self-cleavage rates at a single embedded ribonucleoside site. Previous works relied on three functional groups: an amine, a guanidine and an imidazole ensconced on three different nucleosides. However, to date, few studies have systematically addressed the necessity of all three modifications, as the value of any single modified nucleoside is contextualized at the outset of selection. Herein, we report on the use of only two modified dNTPs, excluding an imidazole, i. e. 5-(3-guanidinoallyl)-2'-dUTP (dUga TP) and 5-aminoallyl-2'-dCTP (dCaa TP), to select in-vitro self-cleaving DNAzymes that cleave in the absence of M2+ in a pH-independent fashion. Cleavage shows biphasic kinetics with rate constants that are significantly higher than in unmodified DNAzymes and compare favorably to certain DNAzymes involving an imidazole.

The Role of BiP and the IRE1α-XBP1 Axis in Rhabdomyosarcoma Pathology.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, and is associated with a poor prognosis in patients presenting with recurrent or metastatic disease. The unfolded protein response (UPR) plays pivotal roles in tumor development and resistance to therapy, including RMS. METHODS: In this study, we used immunohistochemistry and a tissue microarray (TMA) on human RMS and normal skeletal muscle to evaluate the expression of key UPR proteins (GRP78/BiP, IRE1α and cytosolic/nuclear XBP1 (spliced XBP1-sXBP1)) in the four main RMS subtypes: alveolar (ARMS), embryonal (ERMS), pleomorphic (PRMS) and sclerosing/spindle cell (SRMS) RMS. We also investigated the correlation of these proteins with the risk of RMS and several clinicopathological indices, such as lymph node involvement, distant metastasis, tumor stage and tumor scores. RESULTS: Our results revealed that the expression of BiP, sXBP1, and IRE1α, but not cytosolic XBP1, are significantly associated with RMS (BiP and sXBP1 p-value = 0.0001, IRE1 p-value = 0.001) in all of the studied types of RMS tumors (n = 192) compared to normal skeletal muscle tissues (n = 16). In addition, significant correlations of BiP with the lymph node score (p = 0.05), and of IRE1α (p value = 0.004), cytosolic XBP1 (p = 0.001) and sXBP1 (p value = 0.001) with the stage score were observed. At the subtype level, BiP and sXBP1 expression were significantly associated with all subtypes of RMS, whereas IRE1α was associated with ARMS, PRMS and ERMS, and cytosolic XBP1 expression was associated with ARMS and SRMS. Importantly, the expression levels of IRE1α and sXBP1 were more pronounced in ARMS than in any of the other subtypes. The results also showed correlations of BiP with the lymph node score in ARMS (p value = 0.05), and of sXBP1 with the tumor score in PRMS (p value = 0.002). CONCLUSIONS: In summary, this study demonstrates that the overall UPR is upregulated and, more specifically, that the IRE1/sXBP1 axis is active in RMS. The subtype and stage-specific dependency on the UPR machinery in RMS may open new avenues for the development of novel targeted therapeutic strategies and the identification of specific tumor markers in this rare but deadly childhood and young-adult disease.

Synthesis and evaluation of "Ama-Flash", a photocaged amatoxin prodrug for light-activated RNA Pol II inhibition and cell death.

Amanitin is used extensively as a research tool to inhibit RNA Pol II thereby implicating its role in mRNA transcription. Recently, amanitin has gained traction as a toxic payload for targeted therapy. Here we report the first-ever photocaged amanitin analog, that is non-toxic and can be pre-loaded into cells. Light provides a means to inhibit RNA Pol II and provoke cell death on-demand.

A bioengineering method for modeling alveolar Rhabdomyosarcoma and assessing chemotherapy responses.

Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue malignant tumor. Treatment of RMS usually includes primary tumor resection along with systemic chemotherapy. Two-dimensional (2D) cell culture systems and animal models have been extensively used for investigating the potential efficacy of new RMS treatments. However, RMS cells behave differently in 2D culture than in vivo, which has recently inspired the adoption of three-dimensional (3D) culture environments. In the current paper, we will describe the detailed methodology we have developed for fabricating a 3D engineered model to study alveolar RMS (ARMS) in vitro. This model consists of a thermally cross-linked collagen disk laden with RMS cells that mimics the structural and bio-chemical aspects of the tumor extracellular matrix (ECM). This process is highly reproducible and produces a 3D engineered model that can be used to analyze the cytotoxicity and autophagy induction of drugs on ARMS cells. The most improtant bullet points are as following:•We fabricated 3D model of ARMS.•The current ARMS 3D model can be used for screening of chemotherapy drugs.•We developed methods to detect apoptosis and autophagy in ARMS 3D model to detect the mechansims of chemotherapy agents.

Pitolisant, a wake-promoting agent devoid of psychostimulant properties: Preclinical comparison with amphetamine, modafinil, and solriamfetol.

Several therapeutic options are currently available to treat excessive daytime sleepiness (EDS) in patients suffering from narcolepsy or obstructive sleep apnea. However, there are no comparisons between the various wake-promoting agents in terms of mechanism of action, efficacy, or safety. The goal of this study was to compare amphetamine, modafinil, solriamfetol, and pitolisant at their known primary pharmacological targets, histamine H3 receptors (H3R), dopamine, norepinephrine, and serotonin transporters, and in various in vivo preclinical models in relation to neurochemistry, locomotion, behavioral sensitization, and food intake. Results confirmed that the primary pharmacological effect of amphetamine, modafinil, and solriamfetol was to increase central dopamine neurotransmission, in part by inhibiting its transporter. Furthermore, solriamfetol increased levels of extracellular dopamine in the nucleus accumbens, and decreased the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA ratio in the striatum, as reported for modafinil and amphetamine. All these compounds produced hyperlocomotion, behavioral sensitization, and hypophagia, which are common features of psychostimulants and of compounds with abuse potential. In contrast, pitolisant, a selective and potent H3R antagonist/inverse agonist that promotes wakefulness, had no effect on striatal dopamine, locomotion, or food intake. In addition, pitolisant, devoid of behavioral sensitization by itself, attenuated the hyperlocomotion induced by either modafinil or solriamfetol. Therefore, pitolisant presents biochemical, neurochemical, and behavioral profiles different from those of amphetamine and other psychostimulants such as modafinil or solriamfetol. In conclusion, pitolisant is a differentiated therapeutic option, when compared with psychostimulants, for the treatment of EDS, as this agent does not show any amphetamine-like properties within in vivo preclinical models.

Chiral Benzothiazole Monofluoroborate Featuring Chiroptical and Oxygen-Sensitizing Properties: Synthesis and Photophysical Studies.

Advances in personalized medicine are prompting the development of multimodal agents, that is, molecules that combine properties promoting various diagnostic and therapeutic applications. General approaches exploit chemical conjugation of therapeutic agents with contrast agents or the design of multimodal nanoplatforms. Herein, we report the design of a single molecule that exhibits potential for different diagnostic modes as well as the ability to sensitize oxygen, thus offering potential for photodynamic therapy. Exceptionally, this work involves the synthesis and chiral resolution of an enantiomeric pair of chiral monofluoroborates that contain a stereogenic boron atom. Combining experimental and theoretical chiroptical studies allowed the unambiguous determination of their absolute configuration. Photophysical investigations established the ability of this compound to sensitize oxygen even in the absence of heavy atoms within its structure. The synthesis of a chiral benzothiazole monofluoroborate paves a way to multimodal diagnostic tools (fluorescence and nuclear imaging) while also featuring potential therapeutic applications owing to its ability to activate oxygen to its singlet state for use in photodynamic therapy.